KR101085315B1 - Amino acid phenoxy ethers - Google Patents

Abstract

Novel amino acid phenyl ethers are provided which exhibit activity for the treatment of immunological diseases, inflammation, obesity, hyperlipidemia, hypertension, neurological diseases and diabetes.

Description

Amino Acid Phenoxy Ether {AMINO ACID PHENOXY ETHERS}

This application claims priority to US divided application 60 / 440,772, filed January 17, 2003.

The present invention relates to novel amino acid phenyl ethers for the treatment of immunological diseases, inflammation, obesity, hyperlipidemia, hypertension, neurological diseases, diabetes.

Key elements of the immune system are macrophages or antigen-presenting cells, T cells, B cells. Although the function of other immune cells such as NK cells, basophils, mast cells, dendritic cells is known, their role in primary immunological diseases is not clear. Macrophages are important mediators of inflammation and provide the "help" required for T cell stimulation and proliferation. Most importantly, macrophages produce IL-1, IL-12, TNF-α, all of which are potent pro-inflammatory molecules and provide help to T cells. In addition, macrophage activation leads to the induction of enzymes such as cyclooxygenase II (COX-2), inducible nitric oxide synthase (iNOS) and free radicals that can damage normal cells. May cause production. Most factors activate macrophages, including bacterial products, superantigens and interferon gamma (IFN-γ). Phosphotyrosine kinases (PTKs) and other unidentified cellular kinases are believed to be involved in the activation process.

Cytokines are molecules secreted by immune cells that play an important role in mediating the immune response. Cytokine production induces the secretion of other cytokines, modified cell function, cell division or differentiation. Inflammation is a normal response to injury or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathological inflammatory processes can lead to morbidity and mortality. Cytokine Tumor Necrosis Factor-alpha (TNF-α) plays a central role in the inflammatory response and is a target of intervention in inflammatory diseases. TNF-α is a polypeptide hormone released by activated macrophages and other cells. At low concentrations, TNF-α participates in a protective inflammatory response by activating leukocytes and promoting their migration to extravascular inflammation sites (Moser et al., J Clin Invest, 83: 444-55,1989). At high concentrations, TNF-α functions as a potent pyrogen and can induce the production of other pro-inflammatory cytokines (Haworth et al., Eur J hnmunol, 21: 2575-79, 1991; Brennan et al., Lancet, 2: 244-7, 1989). TNF-α also stimulates the synthesis of acute phase proteins. In rheumatoid arthritis, a chronic and progressive inflammatory disease that adversely affects approximately 1% of the US adult population, TNF-α mediates a cytokine cascade that causes joint damage and destruction (Arend et al., Arthritis Rheum, 38: 151-). 60,1995). Recently, soluble TNF receptors (Goldenberg, Clin Ther, 21: 75-87, 1999) and anti-TNF-α antibodies (infliximab) (Luong et al., Ann Pharmacother, 34: 743-60, 2000) Inhibitors of TNF-α have been approved by the US Food and Drug Administration as a treatment for rheumatoid arthritis.

Elevated TNF-α levels are also involved in cachexia, pulmonary shock syndrome, osteoarthritis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.

Since excessive production of IL-6 is involved in several disease states, it is highly desirable to develop compounds that inhibit IL-6 secretion.

Cytokine IL-1β also participates in the inflammatory response. It stimulates thymic cell proliferation, fibroblast growth factor activity, release of prostaglandins from synovial membrane cells.

Elevated or modest levels of cytokine IL-1β are associated with various inflammatory diseases and other disease states, including adult respiratory distress syndrome, allergies, Alzheimer's disease and the like.

Since overproduction of IL-1β is associated with various diseases, it is desirable to develop compounds that inhibit the production or activity of IL-1β.

As described above, to provide a compound that inhibits TNF-α, IL-1, IL-6, COX-2 or other agonists that are considered to be the cause of an immune response, inflammatory or inflammatory disease, such as arthritis Despite many efforts, there is still a need for new and improved compounds that effectively treat or inhibit such diseases.

TNF-α appears to correlate with adipocyte formation (obesity) and other metabolic disorders such as diabetes. Although the number of diabetics has exploded worldwide over the past 20 years [Amos A., McCarty, D., Zimmet, P. (1997) Diabetic Med. 14, S1-S85; King, H., Aubert, R., Herman, W. (1998) Diabetes Care, 21, 1414-1431], the development of new therapeutics for diabetes and related diseases has been rarely done [Moller, DE (2001) Nature 414, 821-827. Diabetes exists in two types: insulin dependent type I and non-insulin dependent (insulin-resistant) type II. Type II insulin-resistant diabetes accounts for 90-95% of all diabetes. Currently, these syndromes are adversely affecting 150 million people worldwide and are expected to increase to 300 million by 2005 [Amos, A., McCarty, D., Zimmet, P. (1997). Diabetic Med. 14, S1-S85, Kopelman, P.G. Hitaman, G. A. (1998) Lancet, 352, SIV 5]. The main driver of this increase in the incidence of type II diabetes is the increase in obesity, the most important cause of the pathogenesis of type II diabetes.

To date, treatment for type II diabetes relies mainly on several ways of reducing hyperglycemia itself. These include sulfonylureas and related insulin secretogens known to release more insulin from pancreatic β cells; Metformin, which functions to reduce hepatic glucose production; Peroxysomal proliferator-activated receptor (PPAR) agonists to enhance insulin action; Α-glucosidase inhibitors that delay absorption of glucose from the gut; It is insulin itself that inhibits glucose production and enhances glucose utilization (Table I below). Both of these treatments have limited efficacy, limited tolerability, and significant mechanism-based side effects. Of particular concern is that most treatments tend to boost body weight gain. Some current type II diabetes treatments are associated with hypoglycemia and very few are available as therapeutics that adequately address basic deficiencies such as the phenomenon known as obesity and insulin resistance. Of these oral drugs, sulfonylureas are the oldest and most widely used therapeutics. Most patients who initially respond to sulfonyl urea do not respond to it over time (secondary failure). In addition to glucose levels and obesity, type II diabetes is associated with high levels of triglycerides and cholesterol. For this reason, there is a need for a new class of drugs to treat type II diabetes and related diseases by addressing underlying metabolic defects such as obesity, hyperglycemia, hyperlipidemia.

Table 1. Agonists Currently Used in Type II Diabetes

Drug Type relay molecule Site of action Side Effect insulin Intramuscular Insulin receptor Liver, muscle, fat Weight gain
Hypoglycemia Sulfonylurea
(Glibenclamide)
(Repaglinide)
(Nateglinide) oral- SU receptor
K + / ATP Channel Pancreatic β cells Weight gain
Hypoglycemia Metformin
(Biguanides) oral- Unknown Liver (Muscle) GI disturbance
Lactic acidosis α-glucosidase inhibitor
(Acarbose) oral- α-glucosidase chapter GI disturbance PPAR-Agonists
(Rosiglitazone)
(Pioglitazone) oral- PPAR-gamma Fat, muscle, liver Weight gain
anemia
edema

SUMMARY OF THE INVENTION

The present invention relates to novel amino acid phenyl ethers of formula (I), derivatives thereof, analogues thereof, tautomeric forms thereof, stereoisomers thereof, homogeneous thereof, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates thereof All:

Where ---- represents an optional double bond;

Y represents oxygen, sulfur or NR, and R represents hydrogen or alkyl;

Z represents oxygen or sulfur;

R ₁ , R ₂ , R ₃ , R ₄ are the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy;

A represents a single bond or a substituted or unsubstituted aryl, heterocyclyl or heteroaryl ring;

X represents an alpha amino carboxylic acid or derivative thereof bonded to A or Y via an alpha side chain.

The present invention also provides the above-described novel compounds, derivatives thereof, analogs thereof, tautomeric forms thereof, stereoisomers thereof, homogeneous thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, novel intermediates It relates to a process for the preparation of substances, pharmaceutical compositions containing them. Tautomeric forms are equilibrium isomeric forms that can react in any form. Stereoisomers encompass coordination isomers such as cis- and trans-double bonds and optically active isomers that possess different spatial alignment of atoms. Homogeneity is a molecule that can be crystallized in two or more forms. Solvent compounds are molecules or ions of a solvent and molecules or ions complexes of molecules or ions of a solute. Alpha-amino carboxylic acids encompass naturally-occurring amino acids. The alpha side chain is a functional group covalently bonded to the alpha carbon of the alpha-amino carboxylic acid, for example hydrogen. Analogs encompass compounds distinguished by substitution of oxygen, sulfur, nitrogen or carbon atoms. Analogs also carry atoms of the same family in the periodic table, such as F, Cl, Br, I, As. Derivatives encompass compounds resulting from the conventional functionalization of atoms, for example derivatives generated by protective amino groups or carboxyl groups in carboxylation or esterification reactions, respectively.

The compounds of the present invention are effective for lowering blood sugar, serum insulin, free fatty acids, cholesterol, triglyceride levels, and are useful for the treatment and / or prevention of diabetes. The compounds of the present invention are effective in the treatment of obesity, inflammation, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Surprisingly, these compounds have no hepatotoxicity while increasing leptin levels.

Furthermore, the compounds of the present invention can be used for the treatment of diseases associated with insulin resistance (eg polycystic ovary syndrome), hyperlipidemia, coronary sinus disease, peripheral vascular disease and inflammatory and immune diseases, in particular TNF-α, IL-1, IL- 6, is effective in the treatment of diseases mediated by cytokines such as IL-1β, cyclooxygenase (eg, COX-2).

Figure 1 shows that in Example 1 compounds 1 and 2 inhibit pro-inflammatory cytokines in human macrophages.

2 shows the efficacy of compound 2 in Example 1 in an inflammatory animal model.

3 shows the efficacy of compounds 1 and 2 in Example 1 in an autoimmune animal model.

4 schematically shows their role in the management of various cytokines and numerous inflammatory and autoimmune diseases.

5 schematically shows how TNF-α is associated with various metabolic disorders in addition to inflammation and autoimmune properties.

FIG. 6 shows the glycemic-enhancing effect of Compound 2 in Example 1 in ob / ob and db / db mice.

FIG. 7 shows the effects of compounds 1 and 2 in Example 1 on decreasing weight gain in obese animal models.

8 shows the effect of compound 2 in Example 1 on insulin sensitization and lipid lowering activity.

9 shows the effect of lipid accumulation in human preadipocytes treated with the compounds of the present invention at various doses compared to rosiglitazone.

In one embodiment of the invention, the functional groups represented by R ₁ , R ₂ , R ₃ , R ₄ are hydrogen; Halogen such as fluorine, chlorine, bromine or iodine; Hydroxy; Nitro; Cyano; Formyl; Amino; Linear or branched, substituted or unsubstituted (C ₁ -C ₁₂ ) alkyl groups, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, nonyl Etc; Substituted or unsubstituted (C ₁ -C ₁₂ ) alkoxy groups such as methoxy, ethoxy, propoxy, butoxy and the like.

In another embodiment of the present invention, the functional group represented by A is aryl such as phenyl, naphthyl and the like; Heteroaryl rings such as pyridyl, pyrrolyl, thiazolyl, indolyl, imidazolyl, furyl and the like; Heterocyclyl rings such as piperazine, morpholine, piperidine, pyrrolidine and the like. A may be single, double or triple substituted and the substituents are selected from halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, haloalkyl, alkoxy, haloalkoxy and the like.

In one embodiment of the invention, the amino acids and side chains represented by X, XA or XAY are substituted or unsubstituted alanine, glycine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, Methionine, ornithine, proline, serine, threonine, tryptophan, tyrosine and derivatives thereof, such as esters and amides of carboxylic acids. Preferred substituents are selected from halogen, alkyl, alkoxy, aryl, heteroaryl, amino and the like.

Suitably, amino acids X-A-Y represent substituted or unsubstituted arginine, asparagine, cysteine, glutamine, histidine, lysine, methionine, ornithine, proline, serine, threonine, tryptophan, tyrosine, derivatives thereof. Suitably, X-A represents alanine, glycine, isoleucine, leucine, derivatives thereof. In another embodiment, A represents a substituted or unsubstituted alkyl, heterocyclyl or heteroaryl ring.

In other embodiments, Z is sulfur and Y is oxygen. Suitably, R ₁ to R ₄ are hydrogen.

Pharmaceutically acceptable salts that form part of the invention include alkaline metal salts such as Li, Na, K salts; Alkaline earth metal salts such as Ca and Mg salts; Salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like; Base addition salts such as ammonium or substituted ammonium salts. Salts are acid addition salts, for example sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartarates, malates, citrates, succinates, pamolates, methanesulfonates, benzoates, salicylic acids Salts, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates are hydrates or contain other crystallization solvents such as alcohols.

Suitably, the present invention provides novel amino acid phenyl ethers of formula I, derivatives thereof, analogs thereof, tautomeric forms thereof, stereoisomers thereof, homogeneous thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts thereof. Regarding Solvent Compounds:

Formula I

Where ---- represents an optional double bond;

Y represents oxygen, sulfur or NR, and R represents hydrogen or alkyl;

Z represents oxygen or sulfur;

R ₁ , R ₂ , R ₃ , R ₄ are the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy;

A represents substituted or unsubstituted aryl;

X represents an alpha amino carboxylic acid or derivative thereof bonded to A via an alpha side chain.

More suitably, the present invention provides novel amino acid phenyl ethers of formula I, derivatives thereof, analogs thereof, tautomeric forms thereof, stereoisomers thereof, homogeneous thereof, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof. Regarding possible solvates:

Formula I

Where ---- represents an optional double bond;

Y represents oxygen, sulfur or NR, and R represents hydrogen or alkyl;

Z represents oxygen or sulfur;

R ₁ , R ₂ , R ₃ , R ₄ are the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy;

A represents substituted or unsubstituted phenyl;

X represents alanine or a derivative thereof bonded to A via an alpha methyl group.

Particularly useful compounds according to the invention are selected below:

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,6-difluorobenzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,6-difluorobenzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,6-difluorobenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,6-difluorobenzyl] oxazolidine-2,4 dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,6-difluorobenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,6-difluorobenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,6-difluorobenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,6-difluorobenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,3-difluorobenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,3-difluorobenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,3-difluorobenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,3-difluorobenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,3-difluorobenzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,3-difluorobenzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,3-difluorobenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,3-difluorobenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-methylbenzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-methylbenzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-methylbenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-methylbenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-methylbenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-methylbenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-methylbenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-methylbenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-nitrobenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-nitrobenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-nitrobenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-nitrobenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-nitrobenzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-nitrobenzylidene] oxazolidine-2,4 dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-nitrobenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-nitrobenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-aminobenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-aminobenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-aminobenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-aminobenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxyj-3-aminobenzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-aminobenzylidene] oxazolidine-2,4 dione or salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-aminobenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-aminobenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-fluorobenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-fluorobenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-fluorobenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-fluorobenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-fluorobenzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-fluorobenzylidene] oxazolidine-2,4 dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-fluorobenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-fluorobenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-fluorobenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-fluorobenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-fluorobenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-fluorobenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-fluorobenzylidene] oxazolidine-2,4-dione or salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-fluorobenzylidene] oxazolidine-2,4 dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-fluorobenzyl] oxazolidine-2,4-dione or salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-fluorobenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-trifluoromethylbenzylidene] thiazolidine-2,4 dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-trifluoromethylbenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-trifluoromethylbenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-trifluoromethylbenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-trifluoromethylbenzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-trifluoromethylbenzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-trifluoromethylbenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-trifluoromethylbenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-trifluoromethylbenzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-trifluoromethylbenzylidene] thiazolidine-2,4-dione or a salt thereof;

5-4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-trifluoromethylbenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-trifluoromethylbenzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-trifluoromethylbenzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-trifluoromethylbenzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-trifluoromethylbenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-trifluoromethylbenzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2,6-difluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,6-difluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2,6-difluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,6-difluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2,6-difluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,6-difluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2,6-difluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,6-difluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2,3-difluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,3-difluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2,3-difluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,3-difluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2,3-difluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,3-difluorophenoxy) benzylidene] -oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2,3-difluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,3-difluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-methylphenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-methylphenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-methylphenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-methylphenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-methylphenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-methylphenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-methylphenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-methylphenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-nitrophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-nitrophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-nitrophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-nitrophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-nitrophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-nitrophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-nitrophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-nitrophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-aminophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-aminophenoxy) benzylidene] thiazolidine-2,4 dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-aminophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-aminophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-aminophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-aminophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-aminophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-aminophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2-fluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-fluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2-fluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-fluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2-fluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-fluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2-fluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-fluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-fluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-fluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-fluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-fluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-fluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-fluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-fluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-fluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2-trifluoromethylphenoxy) benzylidene] thiazolidine-2,4 dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-trifluoromethylphenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2-trifluoromethylphenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-trifluoromethylphenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2-trifluoromethylphenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-trifluoromethylphenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -2-trifluoromethylphenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-trifluoromethylphenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-trifluoromethylphenoxy) benzylidene] thiazolidine-2,4 dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-trifluoromethylphenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-trifluoromethylphenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-trifluoromethylphenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-trifluoromethylphenoxy) benzylidene] oxazolidine-2,4 dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-trifluoromethylphenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-carboxyethyl) -3-trifluoromethylphenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-trifluoromethylphenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-t-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-t-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzyl] thiazolidine-2,4 dione or a salt thereof;

5- [4- (4- (2-t-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-t-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof.

5- [4- (4- (2-t-butoxycarbonylamino-2-carboxyethyl) phenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-t-butoxycarbonylamino-2-carboxyethyl) phenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-t-butoxycarbonylamino-2-carboxyethyl) phenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof;

5- [4- (4- (2-t-butoxycarbonylamino-2-carboxyethyl) phenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof.

Preferred salts of the above compound list are hydrochloride, hydrobromide, sodium salts, potassium or magnesium salts.

According to another feature of the invention, as shown in Scheme I,-it provides a process for the preparation of compounds of formula I in which ---- represents a single bond and all other symbols are as defined above:

In the presence of a solvent such as THE, DMF, DMSO, DME or mixtures thereof, the compound of formula IIIa (X ₁ represents a protected alpha amino carboxyl group and all other symbols are as defined above) and the compound of formula IIIb (L is A nucleophilic aromatic substituted leaving group and all other symbols are the same as defined above) to give the compound of formula IIIc. This reaction is carried out in an inert atmosphere maintained by using an inert gas, for example N ₂ , Ar or He. The reaction is carried out in the presence of a base such as K ₂ CO ₃ , Na ₂ CO ₃ , NaH or mixtures thereof. The reaction temperature is 20 ° C to 150 ° C, preferably 30 ° C to 100 ° C. The duration of the reaction is 1 to 24 hours, preferably 2 to 6 hours.

Conventional protecting groups used can be easily removed and are selected from t-Boc, CBz, F-moc and the like.

Formula IIId by reacting a compound of Formula IIIc with 2,4-thiazolidinedione or 2,4-oxazolidinedione in the presence of sodium acetate or in the presence of a solvent such as benzene, toluene, methoxyethanol or mixtures thereof Obtain the compound. The reaction temperature is from 80 ° C. to 180 ° C., and the reaction is carried out in the presence of sodium acetate. Catalysts such as piperidinium acetate, benzoate, sodium acetate, or mixtures of catalysts may also be used. Sodium acetate can be used in the presence of a solvent, but is preferably used alone. The water produced in this reaction can be removed using, for example, Dean Stark water separators or water absorbing agents such as molecular sieves.

Compound (I) is obtained by deprotecting the amino group of formula (IIId) with an acid such as HCl, sulfuric acid, acetic acid in the presence of a solvent such as DCM, ethyl acetate, water or mixtures thereof at temperatures ranging from -10 ° C to 50 ° C. do.

In another embodiment of the present invention, compounds of formula I, wherein Z is sulfur and ---- is no bond, can be prepared by reacting a compound of formula IIIe with thiourea and then with acid:

Wherein J is a halogen atom such as chlorine, bromine or iodine and R is a lower alkyl group.

The reaction of the compound of formula IIIe with thiourea is carried out in the presence of an alcoholic solvent such as methanol, ethanol, propanol, isobutanol, 2-methoxybutanol, DMSO or sulfolane. The reaction is carried out at 20 ° C. to the reflux temperature of the solvent used. Bases such as NaOAc, KOAc, NaOMe, NaOEt and the like can be used.

In another embodiment of the present invention, the compound of formula I, wherein ---- is a single bond and all other symbols are as defined above, can be prepared by reacting a compound of formula IIIf with a compound of formula IIIg:

Where L is a nucleophilic leaving group, for example a halogen atom such as chlorine, bromine or iodine; Methanesulfonic acid salts; Trifluoromethanesulfonate; p-toluene sulfonate, and the like,

In the presence of a solvent such as THE, DMF, DMSO, DME or a mixture thereof, the compound of formula IIIf and the compound of formula IIIg are reacted to give a compound of formula I. This reaction is carried out in an inert atmosphere maintained by using an inert gas, for example N ₂ , Ar or He. The reaction may be alkali, such as sodium or potassium hydroxide; Alkali metal carbonates such as sodium carbonate or potassium carbonate; Alkali metal hydrides such as sodium hydride; Organometallic bases such as n-butyl lithium; It is carried out in the presence of a base, such as an alkali metal amide, for example sodaamide, or a mixture thereof. Plural solvents and bases may be used. The amount of base is 1 to 5 equivalents, preferably 1 to 3 equivalents. The reaction temperature is 0 ° C to 120 ° C, preferably 20 ° C to 100 ° C. The duration of the reaction is 0.5 to 24 hours, preferably 0.5 to 6 hours.

In another embodiment of the present invention, the compound of formula I, wherein ---- is a single bond and all other symbols are as defined above, can be prepared by reacting a compound of formula IIIh with a compound of formula IIIg:

Where A and X are the same as defined above,

Chemical formula IIIg

In the presence of a solvent such as THE, DMF, DMSO, DME or a mixture thereof, the compound of formula IIIh and the compound of formula IIIg are reacted to give a compound of formula I. This reaction is carried out in an inert atmosphere maintained by using an inert gas, for example N ₂ , Ar or He. The reaction may be alkali, such as sodium or potassium hydroxide; Alkali metal carbonates such as sodium carbonate or potassium carbonate; Alkali metal hydrides such as sodium hydride; Organometallic bases such as n-butyl lithium; It is carried out in the presence of a base such as an alkali metal amide such as sodamide, or a mixture thereof. Plural solvents and bases may be used. The amount of base is 1 to 5 equivalents, preferably 1 to 3 equivalents. The reaction temperature is 0 ° C to 120 ° C, preferably 20 ° C to 100 ° C. The duration of the reaction is 0.5 to 24 hours, preferably 0.5 to 6 hours.

According to another embodiment of the present invention, there is provided a process for preparing a compound of formula (I) in which ---- is no bond by reducing compound of formula (I) where ---- is a single bond and all other symbols are as defined above. . This reduction is carried out in the presence of gaseous hydrogen and catalysts such as Pd / C, Rh / C, Pt / C, Raney Nickel and the like. Catalyst mixtures may be used. The reaction is carried out in the presence of a solvent such as dioxane, acetic acid, ethyl acetate and the like. Solvent mixtures may be used. Pressures from atmospheric to 100 psi are used. The catalyst is 5-10% Pd / C and the amount of catalyst used is 50-300% w / w. The reaction may also be carried out by metal solvent reduction such as magnesium in methanol or sodium amalgam in methanol. The reaction is in the presence of cobalt and ligands, such as CoCl ₂ , preferably bidentate ligands such as 2,2′-bipyridyl, 1,10-phenanthroline, bisoxime and the like. Under alkali metal borohydride such as LiBH ₄ , NaBH ₄ , KBH ₄ and the like.

In another embodiment of the invention, the intermediate of formula IIIc, derivative thereof, analog thereof, tautomeric form thereof, stereoisomer thereof, homogeneous thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable thereof Solvent Compounds:

Wherein Y represents oxygen, sulfur or NR and R represents hydrogen or alkyl;

R ₁ , R ₂ , R ₃ , R ₄ are the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy;

A represents substituted or unsubstituted aryl;

X represents an alpha amino carboxylic acid or derivative thereof bonded to A via an alpha amino side chain.

In another embodiment of the invention, the intermediate of formula (IIIe), derivatives thereof, analogs thereof, tautomeric forms thereof, stereoisomers thereof, homogeneous thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvents thereof To present the compound:

Chemical formula IIIe

Wherein Y represents oxygen, sulfur or NR and R represents hydrogen or alkyl;

R ₁ , R ₂ , R ₃ , R ₄ are the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy;

A represents substituted or unsubstituted aryl;

X represents an alpha amino carboxylic acid or derivative thereof bonded to A via an alpha amino side chain;

J represents a halogen atom;

R ₅ represents a lower alkyl group.

Surprisingly, unlike other thiazolidine-compounds (TZD molecules), the compounds of the present invention show no adipocyte differentiation. In addition, its administration reduces body weight gain. Finally, the compounds of the present invention appear to have no affinity for PPAR-γ. These three features of the compounds according to the invention are typically distinguished from known TZD molecules that retain adipocyte differentiation activity, increase body weight and are PPAR-γ agonists. Furthermore, the compounds of the present invention possess anti-inflammatory properties. For example, the compounds of the present invention inhibit TNF-α, IL-6, IL-1β.

The compounds of the present invention are mixed with a physiologically acceptable vehicle in a pharmaceutical composition. A particularly preferred form of the composition is a capsule or solution for oral administration wherein the compound is delivered in water, saline, phosphate buffer, or lyophilized powder in the form of tablets or capsules containing various fillers and binders. The effective amount of the compound in the composition is selected by one skilled in the art and determined empirically.

Compounds of the present invention may be used for diseases such as inflammation, autoimmune diseases (eg, multiple sclerosis), IBD, obesity, neurological diseases, hypertension and elevated blood sugar levels, namely diabetes, such as type I and type II diabetes. It is effective for the treatment of hyperglycemia disorders and other hyperglycemia related disorders such as hyperlipidemia, kidney related disorders and the like.

As used herein, “treatment” refers to administering a compound of the present invention to a patient suffering from such symptoms in order to reduce inflammation, hypertension, obesity, blood lipid levels, blood glucose levels, or symptoms associated with autoimmune or neurological diseases. it means. Compounds of the invention are administered in an amount sufficient to reduce, for example, blood sugar levels to an acceptable range, where the acceptable range is +/- 10%, preferably +/- 8%, of the normal mean blood sugar level in the subject, More preferably +/- 5%. For example, various individuals, including humans, livestock, rare animals, pets, can be treated with the compounds of the present invention. Compounds of the invention are administered to a subject using conventional dosing techniques including intravenous, intradermal, intramuscular, subcutaneous, oral administration and the like. However, the oral route of administration is particularly preferred. The dose delivered to the host is generally between 5 and 500 mg per 70 kg of human body weight, depending on the route of delivery of the compound.

The invention is described in detail in the examples set forth below, which are for illustrative purposes and do not limit the scope of the invention.

Example 1

Preparation of 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzyl] -thiazolidine-2,4-dione hydrochloride

(i) step

Preparation of Methyl-2-[(t-butoxycarbonyl) amino] -3-[-(4-formylphenoxy) phenyl] propanoate

Methyl-2-[(t-butoxycarbonyl) amino] -3- (4-hydroxyphenyl dissolved in DMF (20 mL) in a suspension of sodium hydride (0.813 g, 33.9 mmol) dissolved in dry DMF (20 mL). Propanoate (10 g, 33.9 mmol) solution was added slowly under a nitrogen atmosphere. The mixture was stirred for 15 minutes. 4-Fluorbenzaldehyde (4.20 g, 33.9 mmol) was added and the mixture was heated to 80 ° C. After completion of the reaction, the solvent was removed in high vacuum and the mixture was quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3x50 mL). After washing with brine and drying over anhydrous sodium sulfate, the solvent is evaporated and the product is hexane: ethyl ether; Purification by flash column from eluent 12/30 to 12/22 gave the title compound (yield: 11.5 g, 85.0%) as an oil.

¹ H NMR (CDCl ₃ , 360 M Hz,): δ9.92 (s, 1H), 7.83 (d, 2H), 7.19 (d, 2H), 7.05 (d, 2H), 7.03 (d, 2H), 4.60 (t, 1H), 3.72 (s, 3H), 3.09 (d, 2H), 1.42 (s, 9H). The structure is Mass Spec. Calculated (M + 1) 400.4, Measured 400.3.

(ii) step

Preparation of 5- [4- (4- (2-t-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzylidene] thiazolidine-2,4-dione

Methyl-2-[(t-butoxycarbonyl) amino] -3-[-(4-formylphenoxy) phenyl] prop obtained in step (i) dissolved in anhydrous toluene (10 g, 25 mmol) To the panoate solution, 2,4-thiazolidinedione (3.53 g, 30 mmol) was added sequentially followed by benzoic acid (0.46 g, 3.75 mmol) and piperidine (0.28 g, 3.25 mmol). The solution was heated to reflux at 145-155 ° C. and water was removed for 5 hours using the Dean-Stark apparatus. The solution was cooled to RT and the yellow solid precipitated to give the title compound (yield: 11.9 g, 96%, purity 96.5%, HPLC, mp: 160-164 ° C.).

¹ H NMR (CDCl ₃ 360 M Hz,): 7.82 (s, 1 H), 7.47 (d, 2 H), 7.05 (d, 2H), 7.00 (d, 2H), 6.75 (d, 2H), 5.18 (m , 1H), 4.54 (M, 1H), 3.71 (s, 3H), 3.02 (m, 2H), 3. 00 (m, 2H). 1.42 (s, 9 H). The structure is Mass Spec. Calculated (M + 1) 498.5; Corroborated by Measured 498.5.

(iii) step

Preparation of 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzylidene] thiazolidine-2,4-dione

5- [4- (4- (2-t-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzylidene] thiazolidine-2,4-dione dissolved in DCM (100 mL) 2 g, 4.0 mmol) solution was bubbled at 0 ° C. with HC1 gas. After stirring for 1 hour, the yellow precipitate was filtered off and 1.7 g (3.9 mmol) of HCl-Tyr (C ₆ H ₄ -CH = TDZ) -OMe was obtained (yield: 97.5%, mp: 187-190 ° C). HPLC product purity was 94.5%. Compound 1.

¹ H NMR (D ₂ 0, 360 M Hz,): 7.46 (s, NH, 1H), 7.24 (d, 2H), 7.16 (d, 2H), 6.94 (d, 2H); 6.78 (d, 2H), 4.80 (s, NH3, 3H), 4.40 (m, Cα-H, 1H), 3.80 (s, OMe). The structure is Mass Spec. Calculated (M + 1) 501.5; Corroborated by Measured 501.5.

(iv) step

Preparation of 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzyl] thiazolidine-2,4-dione

5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzylidene] thiazolidine-2,4-dione (0.7 g, 1.6 mmol) in methanol (20 mL) To the solution was added dry Pd / C (0.15 g). After hydrogenation overnight at 40 ° C. at 60 psi, the solution was filtered through Celite and evaporated under reduced pressure to yield the title compound quantitatively. The compound did not show melting in DSC, but showed a color change from capillary to black and shrinks at 97-133 ° C. Compound 2.

Pharmaceutically acceptable salts include compounds of formula I in solvents such as ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol and the like, sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, It is prepared by reacting with 1 to 4 equivalents of a base such as calcium hydroxide, magnesium hydroxide and the like. Organic bases such as lysine, arginine, diethanolamine, choline, guanidine, derivatives thereof may also be used. Alternatively, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, in solvents such as ethyl acetate, ether, alcohol, acetone, THF, dioxane, etc. Acid addition salts can be prepared by treatment with acids such as hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like.

In addition, the present invention, together with conventional carriers, diluents, and the like, which are used pharmaceutically, is one or more compounds of formula (I), tautomeric forms thereof, derivatives thereof, analogs thereof, stereoisomers thereof, homomorphisms thereof, pharmaceuticals thereof To a pharmaceutical composition containing an acceptable salt thereof, a pharmaceutically acceptable solvate thereof.

Such pharmaceutical compositions are generally used in the form of tablets, capsules, powders, syrups, solutions, suspensions, and the like, in fragrances, sweeteners, etc., in suitable solids, liquid carriers or diluents, or in suitable sterile media, which form injectable solutions or suspensions. It contains. These compositions typically contain 1 to 25%, preferably 1 to 15%, of the active compound by weight, with the remainder of the composition being a pharmaceutically acceptable carrier, diluent, excipient or solvent.

Pharmaceutically acceptable carriers include solid filters or diluents and sterile aqueous or organic solutions. In pharmaceutical compositions the active compound is present in an amount sufficient to provide the required dose in the above range. Thus, the compound for oral administration can be mixed with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. Pharmaceutical compositions may, if necessary, contain auxiliary ingredients such as flavors, sweeteners, excipients, and the like. Compounds for extra enteral administration may be mixed with sterile aqueous or organic media to form injectable solutions or suspensions. For example, pharmaceutically-acceptable water-soluble acid addition salts of these compounds, or alkali or alkaline earth metal salts, as well as solutions dissolved in sesame oil, peanut oil, aqueous propylene glycol and the like can be used. Injectable solutions prepared in this way can then be administered intravenously, intraperitoneally, subcutaneously or intramuscularly, with intramuscular administration being preferred in humans.

The pharmaceutical compositions of the present invention are particularly effective for lowering blood sugar, serum insulin and triglyceride levels in a type II diabetic animal model. The pharmaceutical composition of the present invention is also effective in the treatment of obesity, inflammation, autoimmune diseases. Furthermore, the pharmaceutical compositions of the present invention can be used for the treatment of diseases associated with insulin resistance (eg polycystic ovary syndrome), hyperlipidemia, coronary artery disease, peripheral vascular disease and inflammation and immune diseases, in particular TNF-α, IL-1, It is effective in the treatment of diseases mediated by cytokines such as IL-6, cyclooxygenase (eg COX-2).

Protocol for Biological Assay

Compounds of the present invention were tested for activity that lowers inflammatory cytokine levels, chemically-induced inflammation, obesity, blood glucose in different biological activity models. 1-9 show the activity profiles of representative compounds.

Figure 1 Compounds 1 and 2 in Example 1 inhibit the major pro-inflammatory cytokines in human monocyte cells.

Human THP-1 monocyte cells were cultured and incubated with the two compounds of Example 1 at different concentrations. Cells were then challenged with lipopolysaccharide (LPS) for 24 hours at a concentration of 1 μg / ml. Cell supernatants were then analyzed for the presence of TNF-α, IL1β, IL-6 cytokines by antibody directed enzyme-linked immunoassay. As shown in FIG. 1, these example compounds can inhibit the production of three major pro-inflammatory cytokines in a dose-dependent manner. No significant change in cell viability was observed in cells cultured in the presence of maximum concentration of compound. These results strongly suggest that the compound of Example 1 is very effective in reducing the production of pro-inflammatory cytokines.

Figure 2. Compound 2 in Example 1 can reduce carrageenan induced inflammation in rats.

Spegue-Dowley rats with an average body weight of 250 g (6-7 weeks of age) were randomly assigned to the three groups and given a 50 mg / kg oral dose of Example 1 compound. After 30 minutes, carrageenan was administered to the area under the plantar foot of the right hind paw. The control group received an equal volume of water without any compound present. Foot size was measured after 2 and 3 hours. Dexamethasone at the concentration of 5 mg / kg was used as a positive control in this experiment. As shown in FIG. 2, the Example 1 compound can substantially reduce inflammation induced by carrageenan. At 3 o'clock, the effect of Example 1 compound was as effective as dexamethasone (known anti-inflammatory drug that functions through different pathways of action).

Figure 3 Compounds 1 and 2 in Example 1 prevent EAE in mice (multiple sclerosis model).

Multiple sclerosis (MS) is an autoimmune disease and is regulated by cytokine levels. To examine the effect of the compound of Example 1 in the MS model, experimental allergic encepahalomyalitis (EAE) was induced in SJL / J mice. EAE is an autoimmune inflammatory disease of the central nervous system (CNS). Because the disease shows many similarities with human MS, it is used as a model to test the potential efficacy of novel drugs that are available for MS. EAE was induced by injection of spinal cord homogenate where the animals were treated with the example compound. The severity of EAE was established by clinical score of paralysis. As shown in FIG. 3, the new compound treatment group showed complete prevention of EAE. These results suggest the utility of example compounds in the treatment of MS and other neurological diseases.

4. Schematic diagram of cytokine regulation and immune disease.

Macrophages produce various cytokines immediately after stimulation by mitotic sources and other unknown factors. Only a few of these key cytokines are known to be involved in various immunological diseases, including many autoimmune diseases.

5. Direct / indirect association of TNF-α in metabolic disease.

TNF-α is widely established to play an important role in inflammatory and autoimmune diseases, and the available treatment for rheumatoid arthritis is the use of antibodies against TNF-α. In addition, many recent studies predict the possible role of TNF-α in adipocyte physiology and metabolic disorders such as diabetes, obesity, hyperlipidemia, and vascular complications. The above schematics reflect how the regulation of TNF-α affects a number of metabolic diseases and may suggest different pathways for treating these diseases.

6. Compound 2 in Example 1 substantially improves hyperglycemia in diabetic mice.

The hyperglycemic effect of the compound was examined in two spontaneous animal diabetes models (ob / ob and db / db mice). ob / ob mice lack the leptin gene and are considered a typical obesity model. db / db mice possess defective leptin receptors and show hyperglycemia with significant body weight gain. The compound was orally administered to these animals at 5, 10, 50 mg / kg body weight per 15-21 day period. Treatment of ob / ob and db / db diabetic animals resulted in a marked improvement in hyperglycemic status. These results are essentially the same in compound 1.

Figure 7 Compounds 1 and 2 in Example 1 reduce body weight gain in obese animal models.

Leptin knockout mice (ob / ob) are suitable as obesity models in addition to diabetes. To test the efficacy of these compounds on obesity, ob / ob mice were treated with these compounds for 21 days. As shown in FIG. 7, daily treatment of ob / ob mice with a single dose of these compounds resulted in a 35% improvement in body weight gain, suggesting the utility of these compounds in the treatment of obesity. This finding is typically the opposite of using other thiazolidines to gain weight.

8. In Example 1 Compound 2 may improve insulin resistance and lipid homeostasis.

Leptin knockout ob / ob mice are also considered a suitable model for insulin resistance. Treatment of these animals with Compound 2 resulted in a> 70% decrease in serum insulin concentrations. Similarly, a 48% decrease in triglyceride levels and a> 50% decrease in serum cholesterol concentrations were observed in the 15-day treatment study. These results suggest that the compound possesses strong anti-lipid properties and can improve the sensitivity of insulin.

In a separate study, these compounds are non-lipogenic, in contrast to other known thiazolidinediones, and have no (or little) affinity for the peroxysomal proliferator activator receptor-gamma (PPAR-γ). Do not hold These biological findings suggest that the compounds possess novel properties and operate with a completely different mechanism of action than PPAR-γ binding.

Figure 9. Known PPAR-γ agonist rosiglitazone induces lipolysis, whereas Compound 2 does not.

Human subcutaneous preadipocytes were cultured in 96 well plates for 13 days in the presence of a vehicle or different amounts (0.01, 0.1, 1.0, 10 micromoles) of rosiglitazone (BRL) or Compound 2 (BLX). Every 72 hours, the medium was replaced with new compound. Since TNF inhibited the lipoforming process, this was the negative control of this experiment, where co-culture with rosiglitazone induced a significant decrease in lipolysis compared to rosiglitazone alone. On day 13, cells were fixed and stained with Oil Red O to measure lipid (triglyceride) accumulation and images were observed under a microscope. To obtain more quantitative data, Oil Red O was extracted by adding isopropanol and measured spectrophotometrically at 540 nM (indicated on the bar graph). Regardless of the dose, Compound 2 did not cause accumulation of lipids. Rosiglitazone showed a dose-dependent increase in lipid production, which could be inhibited by the addition of TNF-α.

Claims (39)

A compound of formula I, a tautomeric form thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof: Formula I

here, ---- represents a selective double bond; Y represents oxygen; Z represents oxygen or sulfur; R ₁ , R ₂ , R ₃ and R ₄ are the same or different and independently represent hydrogen, halogen, nitro, amino, C ₁ -C ₆ alkyl or CF ₃ ; A represents phenylene optionally substituted with a substituent selected from halogen, nitro, amino, C ₁ -C ₆ alkyl or CF ₃ ; X represents an alpha amino carboxylic acid selected from alanine or a derivative thereof, bonded to A or Y via an alpha side chain, which derivative is an alanine C ₁ -C ₆ alkylester, N- (C ₁ -C ₆ alkoxy- Carbonyl) -alanine, and N- (C ₁ -C ₆ alkoxy-carbonyl) -alanine C ₁ -C ₆ alkylester. The compound of claim 1, wherein XAY- represents an amino acid selected from tyrosine or a derivative thereof, wherein the derivative is tyrosine C ₁ -C ₆ alkylester, N- (C ₁ -C ₆ alkoxy-carbonyl) -tyrosine, and N -(C ₁ -C ₆ alkoxy-carbonyl) -tyrosine C ₁ -C ₆ alkylester. delete delete delete The compound of any of claims 1-2, wherein Z is sulfur and Y is oxygen. The compound of any one of claims 1-2, wherein R ₁ to R ₄ are hydrogen. The compound according to any one of claims 1 to 2, characterized in that --- double bonds are present. The compound according to any one of claims 1 to 2, characterized in that there is no --- double bond. delete delete 3. The compound of claim 2, wherein the derivative comprises an alkyl ester of tyrosine. 13. The compound of claim 12, wherein the ester is a methyl ester. The compound of claim ₁ , wherein R ₁ , R ₂ , R ₃ and R ₄ are hydrogen and Z is sulfur. delete The compound of claim 1, wherein the compound is selected from: 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof. The compound of claim 1, wherein the compound is selected from: 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,6-difluorobenzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,6-difluorobenzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,6-difluorobenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,6-difluorobenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,6-difluorobenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,6-difluorobenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,6-difluorobenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,6-difluorobenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,3-difluorobenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,3-difluorobenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,3-difluorobenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,3-difluorobenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,3-difluorobenzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,3-difluorobenzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2,3-difluorobenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2,3-difluorobenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-methylbenzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-methylbenzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-methylbenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-methylbenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-methylbenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-methylbenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-methylbenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-methylbenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-nitrobenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-nitrobenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-nitrobenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-nitrobenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-nitrobenzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-nitrobenzylidene] oxazolidine-2,4 dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-nitrobenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-nitrobenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-aminobenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-aminobenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-aminobenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-aminobenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-aminobenzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-aminobenzylidene] oxazolidine-2,4 dione or salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-aminobenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-aminobenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-fluorobenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-fluorobenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-fluorobenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-fluorobenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-fluorobenzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-fluorobenzylidene] oxazolidine-2,4 dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-fluorobenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-fluorobenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-fluorobenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-fluorobenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-fluorobenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-fluorobenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-fluorobenzylidene] oxazolidine-2,4-dione or salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-fluorobenzylidene] oxazolidine-2,4 dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-fluorobenzyl] oxazolidine-2,4-dione or salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-fluorobenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-trifluoromethylbenzylidene] thiazolidine-2,4 dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-trifluoromethylbenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-trifluoromethylbenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-trifluoromethylbenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-trifluoromethylbenzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-trifluoromethylbenzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-trifluoromethylbenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-trifluoromethylbenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-trifluoromethylbenzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-trifluoromethylbenzylidene] thiazolidine-2,4-dione or a salt thereof; 5-4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-trifluoromethylbenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-trifluoromethylbenzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-trifluoromethylbenzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-trifluoromethylbenzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-trifluoromethylbenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-trifluoromethylbenzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2,6-difluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,6-difluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2,6-difluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,6-difluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2,6-difluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,6-difluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2,6-difluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,6-difluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2,3-difluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,3-difluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2,3-difluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,3-difluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2,3-difluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,3-difluorophenoxy) benzylidene] -oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2,3-difluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2,3-difluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-methylphenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-methylphenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-methylphenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-methylphenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-methylphenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-methylphenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-methylphenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-methylphenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-nitrophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-nitrophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-nitrophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-nitrophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-nitrophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-nitrophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-nitrophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-nitrophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-aminophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-aminophenoxy) benzylidene] thiazolidine-2,4 dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-aminophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-aminophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-aminophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-aminophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-aminophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-aminophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2-fluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-fluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2-fluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-fluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2-fluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-fluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2-fluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-fluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-fluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-fluorophenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-fluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-fluorophenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-fluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-fluorophenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-fluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-fluorophenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2-trifluoromethylphenoxy) benzylidene] thiazolidine-2,4 dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-trifluoromethylphenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2-trifluoromethylphenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-trifluoromethylphenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2-trifluoromethylphenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-trifluoromethylphenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -2-trifluoromethylphenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-trifluoromethylphenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-trifluoromethylphenoxy) benzylidene] thiazolidine-2,4 dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-trifluoromethylphenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-trifluoromethylphenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-trifluoromethylphenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-trifluoromethylphenoxy) benzylidene] oxazolidine-2,4 dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-trifluoromethylphenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-carboxyethyl) -3-trifluoromethylphenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-trifluoromethylphenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-t-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-t-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzyl] thiazolidine-2,4 dione or a salt thereof; 5- [4- (4- (2-t-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-t-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof. 5- [4- (4- (2-t-butoxycarbonylamino-2-carboxyethyl) phenoxy) benzylidene] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-t-butoxycarbonylamino-2-carboxyethyl) phenoxy) benzyl] thiazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-t-butoxycarbonylamino-2-carboxyethyl) phenoxy) benzylidene] oxazolidine-2,4-dione or a salt thereof; 5- [4- (4- (2-t-butoxycarbonylamino-2-carboxyethyl) phenoxy) benzyl] oxazolidine-2,4-dione or a salt thereof. Formula I

here, ---- represents a selective double bond; Y represents oxygen; Z represents oxygen or sulfur; R ₁ , R ₂ , R ₃ and R ₄ are the same or different and independently represent hydrogen, halogen, nitro, amino, C ₁ -C ₆ alkyl or CF ₃ ; A represents phenylene optionally substituted with a group selected from halogen, nitro, amino, C ₁ -C ₆ alkyl or CF ₃ ; X represents an alpha amino carboxylic acid selected from alanine or a derivative thereof, bonded to A or Y via an alpha side chain, which derivative is an alanine C ₁ -C ₆ alkylester, N- (C ₁ -C ₆ alkoxy- Carbonyl) -alanine, and N- (C ₁ -C ₆ alkoxy-carbonyl) -alanine C ₁ -C ₆ alkylester, A process for preparing the amino acid phenyl ether of formula (I), its tautomeric form, its stereoisomer, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof according to claim 1, comprising the steps of Method characterized in that consisting of: i)

Wherein X ₁ represents a protected amino group and all other substituents are as described above, [Formula IIIb]

Where L represents a nucleophilic aromatic substituted leaving group, and R ₁ , R ₂ and R ₃ are the same as described above; Reacting compound IIIa with compound IIIb to produce compound IIIc; [Formula IIIc]

ii) reacting a compound of formula IIIc with 2,4-thiazolidinedione or 2,4-oxazolidinedione to yield a compound of formula IIId; [Formula IIId]

iii) Deprotection of the amino acid group of formula IIId yields a compound of formula I. delete delete delete delete A pharmaceutical composition for the treatment of obesity, comprising the compound of formula I according to claim 16 and a pharmaceutically acceptable carrier, diluent, excipient or solvate. A pharmaceutical composition for the treatment of an immunological disease selected from the group consisting of autoimmune diseases and hypersensitivity, comprising the compound of formula I according to claim 16 and a pharmaceutically acceptable carrier, diluent, excipient or solvate. The pharmaceutical composition of claim 24, wherein the autoimmune disease is multiple sclerosis. The pharmaceutical composition of claim 24, wherein the autoimmune disease is rheumatoid arthritis. A pharmaceutical composition for the treatment of inflammation comprising the compound of formula I according to claim 16 and a pharmaceutically acceptable carrier, diluent, excipient or solvate. The pharmaceutical composition of claim 27, wherein the inflammation is mediated by cyclooxygenase. delete The pharmaceutical composition of claim 24, wherein the immunological disease is mediated by cytokines. A disease associated with insulin resistance selected from the group consisting of polycystic ovary syndrome, hyperlipidemia, coronary artery disease and peripheral vascular disease, comprising the compound of formula I according to claim 16 and a pharmaceutically acceptable carrier, diluent, excipient or solvate Pharmaceutical Compositions for Treatment. delete delete 18. The compound of claim 16 or 17, wherein the salt is selected from hydrochloride, hydrobromide, sodium salt, potassium salt, or magnesium salt. delete delete delete delete delete

Images